Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
PD-1 blockade inhibits osteoclast formation and murine bone cancer pain
Kaiyuan Wang, … , Matthew J. Hilton, Ru-Rong Ji
Kaiyuan Wang, … , Matthew J. Hilton, Ru-Rong Ji
Published June 2, 2020
Citation Information: J Clin Invest. 2020;130(7):3603-3620. https://doi.org/10.1172/JCI133334.
View: Text | PDF
Research Article Cell biology Neuroscience Article has an altmetric score of 10

PD-1 blockade inhibits osteoclast formation and murine bone cancer pain

  • Text
  • PDF
Abstract

Emerging immune therapy, such as with the anti–programmed cell death–1 (anti–PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1−/−) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1−/− mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1−/− mice. Consistently, these beneficial effects in Pd1−/− mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti–PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.

Authors

Kaiyuan Wang, Yun Gu, Yihan Liao, Sangsu Bang, Christopher R. Donnelly, Ouyang Chen, Xueshu Tao, Anthony J. Mirando, Matthew J. Hilton, Ru-Rong Ji

×

Figure 8

RANKL-induced osteoclastogenesis is promoted by PD-L1 via JNK.

Options: View larger image (or click on image) Download as PowerPoint
RANKL-induced osteoclastogenesis is promoted by PD-L1 via JNK.
(A) Repre...
(A) Representative images of RAW 264.7 cells stained for TRAP. Cells were stimulated with low-dose RANKL (20 ng/mL) and coincubated with human IgG (1 μg/mL), PD-L1 (100 ng/mL), or nivolumab (1 μg/mL) for 6 days. Arrows indicate TRAP+ multinucleated osteoclasts. Scale bar: 50 μm. (B) Quantification for A. n = 3 cultures. (C) Representative images of TRAP staining for BM cultures treated with human IgG (1 μg/mL), PD-L1 (100 ng/mL), or nivolumab (1 μg/mL) for 6 days. MCSF, 20 ng/mL; RANKL, 20 ng/mL. Arrows indicate TRAP+ multinucleated osteoclasts. Scale bar: 50 μm. (D) Quantification for C. n = 3 cultures. (E and F) Representative images (E) and quantification (F) of TRAP staining for primary BM cultures from WT mice or Pd1−/− mice treated with vehicle or PD-L1 (100 ng/mL). n = 3 cultures. Scale bar: 50 μm. (G and H) Western blot showing p-ERK, p-JNK, and p-p38 in BMDM treated with RANKL (20 ng/mL) or RANKL (20 ng/mL) together with PD-L1 (100 ng/mL) at different time points. (G) Representative Western blot bands. (H) Quantification for G. n = 3–4 cultures from 3 or 4 male mice. (I) Western blot showing the effect of nivolumab on PD-L1–enhanced phosphorylation of JNK. n = 3 cultures from 3 male mice. (J and K) Representative images (J) and quantification (K) of TRAP staining of primary BM cultures treated with PD-L1 (100 ng/mL) or SP600125 (10 μM). MCSF, 20 ng/mL; RANKL, 20 ng/mL. Scale bar: 50 μm. Data are represented as mean ± SEM. **P < 0.01; ***P < 0.001, 1-way ANOVA with Bonferroni’s post hoc test (B, D, F, I, and K) and 2-way ANOVA with Bonferroni’s post hoc test (H).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 7 X users
Referenced in 2 patents
71 readers on Mendeley
See more details